Epilepsy & Seizures 4

Question 1

Phenobarbital: Mechanism of action

Answer 1

Binds the γ-aminobutyric acid (GABA)-A receptor and prolongs the opening of the associated chloride channel

Question 2

Phenobarbital: 1) efficacy 2) adverse effects 3) place in therapy

Answer 2

1) effective against focal seizures and generalized tonic-clonic seizures but is not effective against generalized absence seizures.
The parenteral solution has been used effectively for status epilepticus

2)
- Cardiovascular effects:
Hypotension and bradycardia
- CNS effects:
drowsiness, ataxia, vertigo, abnormality in thinking, and memory impairment
- Hypersensitivity reactions (delayed)
- It is not recommended in pregnancy because of teratogenicity with increased risk of cardiac malformations in the exposed fetus
- Respiratory depression
- Suicidal ideation/tendencies

3) Because of its adverse effect on cognitive function and its enzyme induction, phenobarbital is used very infrequently as first-line therapy in developed countries.
However, its low cost and wide availability make it the only affordable AED in much of the developing world

Question 3

Primidone: 1) Mechanism of action 2) efficacy 3) adverse effects 4) place in therapy

Answer 3

1) Primidone is converted in the liver to phenobarbital and phenylethylmalonamide, which is also an active metabolite

2) Primidone is effective against focal seizures and generalized tonic-clonic seizures. Anecdotal evidence also exists of efficacy against myoclonic seizures.
Primidone is also effective in controlling essential tremor.

3) In addition to sedation and other adverse effects of phenobarbital, primidone use is associated with an acute toxic reaction unrelated to phenobarbital, with potentially debilitating drowsiness, dizziness, ataxia, nausea, and vomiting

4) Primidone was the least-tolerated agent in the large cooperative US Department of Veterans Affairs trial comparing the efficacy and tolerability of carbamazepine, phenobarbital, phenytoin, and primidone. As a result, it is infrequently used

Question 4

Phenytoin: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 4

1) Phenytoin binds to the active state of the sodium channel to prolong its fast inactivated state, thus reducing high-frequency firing as might occur during a seizure, while allowing normal action potentials to occur
2) High protein binding
3) Inermediate (long with toxicity)
4) High

Question 5

Phenytoin: 1) efficacy 2) adverse effects

Answer 5

1) Phenytoin is effective against focal seizures and generalized tonic-clonic seizures. Phenytoin is not effective against generalized myoclonic or generalized absence seizures and may even exacerbate these seizures; hence, it is not a drug of choice in idiopathic generalized epilepsy

2)
- Blood dyscrasias
agranulocytosis, granulocytopenia, leukopenia, macrocytosis, megaloblastic anemia, pancytopenia, pure red cell aplasia, and thrombocytopenia with or without bone marrow depression,
- Cardiovascular effects
Hypotension and severe cardiac arrhythmia, such as bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation progressing to asystole, cardiac arrest, and death, may occur with rapid IV administration!!
**The rate of IV administration should not exceed 50 mg/min for phenytoin and 150 mg/min for fosphenytoin.

• CNS effects
  drowsiness, fatigue, and nystagmus disorder to ataxia, incoordination, and slurred speech
• Gingival hyperplasia or overgrowth
• Hepatotoxicity
• Hypersensitivity reactions (delayed)
• Suicidal ideation/tendencies
• Peripheral neuropathy
• drug-induced seizure activity
• purple glove syndrome (may occur following peripheral IV administration of phenytoin. May or may not be associated with drug extravasation)
• enlargement of facial features (including coarsening of facial features)

Question 6

Phenytoin: 1) place in therapy 2) dosage

Answer 6

1) Phenytoin was the most frequently used AED for many years, but its use has declined considerably since the appearance of newer AEDs with improved tolerability and pharmacokinetic profiles.
Other factors in its declining use are its narrow therapeutic window and the challenge in maintaining the recommended therapeutic concentration range without producing toxicity or underdosing because of nonlinear kinetics as well as variable absorption

2)
Loading dose (optional) (phenytoin naive):
Oral (capsule [extended release]): 1 g divided into 3 doses (eg, 400 mg, 300 mg, 300 mg) administered at 2-hour intervals; begin maintenance dose 24 hours after first loading dose.

Maintenance dose:
Oral (capsule [extended release]): Initial: 100 mg 3 to 4 times daily; adjust dose based on response and serum concentrations.
After an effective maintenance dose is established, may consider converting stable patients to once-daily dosing.
To ensure optimal absorption, individual oral doses should not exceed 400 mg

Question 7

Phenytoin pharmacokinetics and drug interactions

Answer 7

• Phenytoin is a potent enzyme inducer that reduces the efficacy of drugs metabolized by the P450 enzyme system
• Phenytoin is also affected by a number of agents that reduce its metabolism and cause it to accumulate.
  These include amiodarone, fluoxetine, fluvoxamine, isoniazid, and azole antifungal agents
• The phenytoin protein-free fraction may increase with hepatic and renal failure, in low-protein states, during pregnancy, in old age, and in the presence of highly protein-bound drugs, such as valproate, that compete for protein binding.
  This is of clinical relevance when decisions are made based on total phenytoin serum concentration

Question 8

Phenytoin (Epanutin) indication

Answer 8

Η φαινυτοΐνη ενδείκνυται για τον έλεγχο όλων των μορφών εστιακής επιληψίας και των γενικευμένων τονικοκλονικών κρίσεων
Ακόμη, η φαινυτοΐνη ενδείκνυται για την πρόληψη και την θεραπεία των σπασμών, που εμφανίζονται κατά τη διάρκεια ή μετά τις νευροχειρουργικές επεμβάσεις κρανίου

Question 9

Fosphenytoin: 1) when is it prefered from phenytoin and 2) adverse effects

Answer 9

1) The phenytoin water-soluble prodrug fosphenytoin is preferred for parenteral use.
It has a lower incidence of local reactions with IV administration.
It is also well absorbed after IM administration, which can be considered in the absence of IV access.

2) When administered intravenously in an awake individual, it may be associated with paresthesia and pruritis, most often in the groin region.
IV administration of either phenytoin or fosphenytoin can be associated with hypotension and arrhythmias

Question 10

Carbamazepine: 1) Mechanism of action 2) half-life 3) potential for pharmacokinetic interactions 4) dosage

Answer 10

1) Carbamazepine’s mechanism of action is similar to that of phenytoin.
It blocks the sodium channel in a voltage-dependent and use-dependent fashion, reducing high-frequency neuronal firing
2) Intermediate (10 to 30 hours)
3) High
4) Αρχικά 100 - 200 mg, μία φορά ή δύο φορές την ημέρα.
Αύξηση της δοσολογίας αργά (200 mg κάθε 4 - 7 ημέρες) μέχρι - γενικά στα 400 mg, 2 - 3 φορές την ημέρα - να επιτευχθεί το άριστο αποτέλεσμα.
Σε ορισμένους ασθενείς 1600 mg την ημέρα μπορεί να είναι κατάλληλα (μέγιστη ημερήσια δόση 1600 mg)

Question 11

Carbamazepine: 1) efficacy and 2) place in therapy

Answer 11

1) effective against focal seizures and generalized tonic-clonic seizures. However, it may exacerbate absence, myoclonic, and atonic seizures.
Hence, it is not a good choice in idiopathic generalized epilepsy.
It has FDA indications for trigeminal neuralgia and for acute mania and bipolar disorder
2) Carbamazepine had the best balance of efficacy and tolerability in the large cooperative US Department of Veterans Affairs study that also included phenytoin, phenobarbital, and primidone.
As a result, it became the standard treatment for focal seizures.
No drug has been demonstrated to be more effective than carbamazepine, but its use has declined with the marketing of new AEDs that have pharmacokinetic advantages.

Lamotrigine, oxcarbazepine, and gabapentin have better tolerability than immediate-release carbamazepine.
Enzyme induction and pharmacokinetic interactions have been issues favoring newer AEDs.
On the other hand, economic considerations favor the less-expensive carbamazepine

Question 12

Carbamazepine (Tegretol) indications

Answer 12

• Απλές ή σύνθετες εστιακές κρίσεις (με ή χωρίς απώλεια συνειδήσεως) με ή χωρίς δευτεροπαθή γενίκευση.
• Γενικευμένοι τονικοκλονικοί σπασμοί καθώς επίσης και συνδυασμοί αυτών των τύπων σπασμών

Το Tegretol είναι κατάλληλο και για μονοθεραπεία και για θεραπεία συνδυασμού.

Άλλες ενδείξεις (μόνο οι από του στόματος μορφές)
Ιδιοπαθής νευραλγία του τριδύμου,
ιδιοπαθής νευραλγία του γλωσσο-φαρυγγικού.
Πρόληψη των υποτροπών της διπολικής διαταραχής.

Question 13

Carbamazepine: adverse effects

Answer 13

• Blood dyscrasias
  aplastic anemia, leukopenia, neutropenia, or thrombocytopenia, eosinophilia, leukocytosis, lymphocytosis, or macrocytosis
• Cardiac effects
  heart failure, sinus tachycardia
• Hepatotoxicity
• Hypersensitivity reactions (delayed)
• Hyponatremia (SIADH)
• Neuropsychiatric effects
  ataxia, dizziness, and drowsiness, as well as psychiatric effects such as anxiety and depression
• Suicidal ideation/tendencies

Question 14

Carbamazepine pharmacokinetics and drug interactions

Answer 14

• Carbamazepine is a potent enzyme inducer, reducing the levels of drugs as well as endogenous substances metabolized by the CYP enzyme system
• Carbamazepine also induces its own metabolism, a process known as autoinduction, which results in increased clearance over 2 to 4 weeks, with shortened half-life and lower serum concentration
• Carbamazepine may accumulate when coadministered with inhibitors of CYP 3A4, such as erythromycin and other macrolide antibiotics (except azithromycin), fluoxetine, propoxyphene, and grapefruit juice.
  Carbamazepine epoxide levels increase with concomitant use of some inhibitors, such as valproate and felbamate

Question 15

Oxcarbazepine: 1) Mechanism of action 2) half-life 3) potential for pharmacokinetic interactions 4) dosage

Answer 15

1) Oxcarbazepine is a structural analogue of carbamazepine, but the minor structural differences have resulted in major differences in metabolism and induction of metabolic pathways.
Like carbamazepine and phenytoin, oxcarbazepine binds to the sodium channel, inhibiting high-frequency repetitive neuronal firing

2) Short (<10 hours)
3) Moderate
4) Oral:
Immediate release: Initial: 300 to 600 mg/day in 2 divided doses. May increase dose by ≤600 mg/day increments at weekly intervals to a maximum dose of 2.4 g/day in 2 to 3 divided doses

Extended release: Initial: 600 mg once daily. May increase dose by 600 mg/day increments at weekly intervals to a maximum dose of 2.4 g/day

Question 16

Oxcarbazepine: 1) efficacy 2) adverse effects 3) place in therapy

Answer 16

1) Oxcarbazepine is effective against focal seizures.
It may exacerbate absence and myoclonic seizures and should be avoided in patients with generalized epilepsy

2)
- Blood dyscrasias
Agranulocytosis, leukopenia, aplastic anemia, pancytopenia, and thrombocytopenia
- Hypersensitivity reactions (delayed)
- Hyponatremia
- Neuropsychiatric effects
cognitive symptoms (eg, psychomotor slowing, lack of concentration, speech disturbance or language problems), dizziness, drowsiness, fatigue, and coordination abnormalities (eg, ataxia and abnormal gait)
- Suicidal ideation

3) Oxcarbazepine is approved as a first-line monotherapy for focal seizures.
Multiple comparative monotherapy trials for new-onset focal epilepsy have demonstrated that oxcarbazepine is equal in efficacy to phenytoin and immediate-release carbamazepine but with possibly superior tolerability.
Combining oxcarbazepine with other classic sodium channel blockers, such as carbamazepine, lamotrigine, and phenytoin, may limit tolerability because of dizziness, diplopia, and ataxia

Question 17

Trileptal indications

Answer 17

Το Trileptal ενδείκνυται για την θεραπεία των εστιακών επιληπτικών σπασμών με ή χωρίς δευτερογενείς γενικευμένους τονικοκλονικούς επιληπτικούς σπασμούς.
Το Trileptal ενδείκνυται για χρήση σαν μονοθεραπεία ή σαν συμπληρωματική θεραπεία, σε ενήλικες και σε παιδιά από 6 ετών και άνω

Question 18

Oxcarbazepine pharmacokinetics and drug interactions

Answer 18

Oxcarbazepine is a weak inducer of CYP 3A4, which is responsible for estrogen metabolism, and reduces the efficacy of the oral contraceptive pill at high doses, usually greater than 900 mg/d.
It is a weak inhibitor of CYP 2C19, thus raising the phenytoin level when used at high doses. It does not induce its own metabolism.
Unlike carbamazepine, it is not affected by CYP 3A4 inhibitors, such as erythromycin, fluoxetine, propoxyphene, and grapefruit juice

Question 19

Eslicarbazepine acetate: 1) Mechanism of action 2) half-life 3) potential for pharmacokinetic interactions 4) dosage

Answer 19

1) it represents a third-generation relative of carbamazepine and oxcarbazepine.
Eslicarbazepine acts by blocking sodium channels and stabilizing the inactive state of the voltage-gated sodium channel.
A 2015 study suggested that, unlike carbamazepine, it may enhance slow inactivation of voltage-gated sodium channels.

2) Intermediate (10 to 30 hours)
3) Moderate
4) Initial: Oral: 400 mg once daily; may initiate treatment at 800 mg once daily if seizure reduction outweighs risk of adverse reactions during initiation. Increase in weekly increments of 400 to 600 mg based on clinical response and tolerability.

Maintenance: Oral: 800 to 1,600 mg once daily

Monotherapy: Consider 800 mg once daily for maintenance therapy in patients not tolerating 1,200 mg once daily.

Adjunctive therapy: Consider 1,600 mg once daily for maintenance therapy in patients not achieving response on 1,200 mg once daily.

Question 20

Eslicarbazepine acetate: 1) efficacy 2) adverse effects 3) place in therapy

Answer 20

1) Eslicarbazepine acetate is effective against focal seizures

2) Eslicarbazepine acetate has adverse effects similar to oxcarbazepine, although less frequent.
The most common dose-related adverse effects are dizziness, somnolence, headache, diplopia, nausea, vomiting, fatigue, and ataxia.
Hyponatremia was less commonly reported than in oxcarbazepine trials.
Rash occurs in up to 3% of individuals at 1200 mg/d

3) Eslicarbazepine acetate was first approved by the FDA as adjunctive treatment for focal seizures.
A monotherapy indication followed after successful completion of a conversion to monotherapy trial.
Like oxcarbazepine, it should be avoided in idiopathic generalized epilepsy.
Theoretical considerations suggest eslicarbazepine acetate could be considered a first-line monotherapy for focal seizures, with tolerability advantages over immediate-release oxcarbazepine.
However, financial considerations may be an obstacle

Question 21

Eslicarvazepine indication (Zebinix)

Answer 21

Zebinix is indicated as:
monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy;
adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset seizures with or without secondary generalisation.

Πλεονέκτημα: δίνεται μία φορά την ημέρα!

Question 22

Valproic acid: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions 5) dosage

Answer 22

1) Valproate has multiple mechanisms of action, including GABA potentiation and blocking of sodium channels
2) High
3) Intermediate (10 to 30 hours)
4) High
5) Η αρχική ημερήσια δοσολογία είναι συνήθως 10-15 mg/kg και στη συνέχεια οι δόσεις ρυθμίζονται ανοδικά έως ότου βρεθεί η βέλτιστη.
Συνήθως αυτό είναι μέσα στο εύρος των 20-30 mg/kg/ημέρα

Question 23

Valproic acid: 1) efficacy 2) place in therapy

Answer 23

1) Valproate has a wide spectrum of efficacy against all focal and generalized seizures, including generalized absence and myoclonic seizures.
The divalproex sodium formulation also has FDA indications for migraine prophylaxis and bipolar disorder

2) Valproate remains the most effective AED for idiopathic generalized epilepsy with generalized tonic-clonic seizures and should remain a drug of first choice for men with generalized epilepsy.
Although equally effective as ethosuximide for generalized absence seizures, it has more cognitive adverse effects.
A large cooperative US Department of Veterans Affairs study found it less well tolerated and less effective than carbamazepine for complex partial seizures (focal impaired awareness seizures), although equally effective for secondarily generalized tonic-clonic seizures (focal to bilateral tonic-clonic seizures)

Question 24

Valproic acid (Depakine) indication

Answer 24

Γενικευμένες τονικοκλονικές επιληπτικές κρίσεις, τυπικές και άτυπες επιληπτικές αφαιρέσεις, εστιακές επιληπτικές κρίσεις, μυοκλονική επιληψία

Συμπληρωματικά με άλλα αντιεπιληπτικά στην αντιμετώπιση ανθεκτικών στη θεραπεία διαφόρων μορφών επιληψίας

Question 25

Valproic acid: adverse effects

Answer 25

• CNS effects
  CNS depression (including dizziness and drowsiness).
  However, nervous system stimulation (eg, nervousness, insomnia, tremor) may also occur at a high frequency in some patients.
  More severe reactions, including delirium and hallucinations have also been reported.
  Parkinsonism!! and cognitive dysfunction
• Hematologic effects
  thrombocytopenia, decreased platelet aggregation, and acquired von Willebrand disease type I may result in hemorrhage in patients receiving valproate.
  Severe complications including hemorrhagic stroke have occurred In some cases
  Other blood disorders including aplastic anemia, neutropenia, and pure red cell aplasia have been reported infrequently
• Hepatotoxicity/hepatic failure
• Hyperammonemia and encephalopathy
• Hypersensitivity reactions (delayed)
• Pancreatitis
• Suicidal ideation/tendencies
• Weight gain!
• Dyslipidemia
• Anovulation
• Hair loss
• Fetal malformation

Question 26

Valproic acid pharmacokinetics and drug interactions

Answer 26

The free fraction increases with increasing total concentration and with coadministration of phenytoin, with which it competes for protein binding.
The half-life in adults is 13 to 16 hours but shorter at about 9 hours with enzyme-inducing drugs.
It is a potent inhibitor, reducing the clearance of phenobarbital, lamotrigine, rufinamide, and carbamazepine epoxide

Question 27

Ethosuximide: 1) Mechanism of action 2) half-life 3) potential for pharmacokinetic interactions

Answer 27

1) Ethosuximide blocks T-type calcium currents, which predicts efficacy against absence seizures
2) Long (>30 hours)
3) Moderate

Question 28

Ethosuximide: 1) efficacy 2) adverse effects 3) place in therapy

Answer 28

1) Ethosuximide is a narrow-spectrum AED, selective for generalized absence seizures

2) Rash, gastrointestinal symptoms, bone marrow suppression

3) Ethosuximide is the AED of choice for absence epilepsy with generalized absence seizures as the only seizure type, a status supported by the large multicenter double-blind randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine

Question 29

Benzodiazepines (Clonazepam and Clobazam): 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions 5) dosage (clobazam)

Answer 29

1) Benzodiazepines act mainly on the GABA-A receptor, increasing the frequency of GABA-mediated chloride channel openings

2) High
3) Intermediate (10 to 30 hours)
4) High
5) Συνιστάται η χορήγηση να αρχίζει με μικρές δόσεις (5-15 mg/ημέρα). Εφόσον είναι αναγκαίο, η δόση αυξάνεται σταδιακά έως τη μέγιστη ημερήσια δόση των 60 mg

Question 30

Benzodiazepines (Clonazepam and Clobazam): 1) efficacy 2) adverse effects 3) place in therapy

Answer 30

1) Both clonazepam and clobazam are broad-spectrum
agents, although their FDA indication is limited to generalized seizure types

2) Drowsiness is a common adverse effect that improves over time.
It is less likely with clobazam.
With increasing doses, nystagmus, incoordination, unsteadiness, and dysarthria may occur.
Tolerance may develop to the therapeutic effect of benzodiazepines, but this appears less likely with clobazam.
Withdrawal seizures may occur with abrupt discontinuation

3) Both clonazepam and clobazam are typically used as adjunctive therapy and have limited data to support monotherapy use.
The clobazam FDA indication is for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome

Question 31

Clobazam (Frisium) indication

Answer 31

Ενδείκνυται ως συμπληρωματικό φάρμακο, για συγχορήγηση με άλλα αντιεπιληπτικά, στις περιπτώσεις εκείνες της επιληψίας που δεν ανταποκρίνονται σε άλλη φαρμακευτική αγωγή

Question 32

Felbamate: 1) Mechanism of action 2) bioavailability 3) protein binding 4) half-life 5) potential for pharmacokinetic interactions

Answer 32

1) It has multiple mechanisms of action, including N-methyl-D-aspartate (NMDA) receptor antagonism, GABA enhancement, and sodium channel blocking
2) Good
3) Low
4) Intermediate (10 to 30 hours)
5) High

Question 33

Felbamate: 1) efficacy 2) place in therapy

Answer 33

1) Felbamate is a broad-spectrum agent effective against focal seizures as well as generalized seizures in the setting of Lennox-Gastaut syndrome

2) Although felbamate was approved for monotherapy, it is not indicated as a first-line treatment because of its potential serious idiosyncratic toxicity.
Adjunctive therapy or alternative monotherapy can be considered when other appropriate and safer options have failed

Question 34

Felbamate: adverse effects

Answer 34

The most common adverse effect of felbamate is gastrointestinal irritation with anorexia, nausea, and vomiting, which can be helped by administration with food.
Felbamate may also cause insomnia, irritability, headache, and weight loss.

The most concerning toxicity is the potentially lethal aplastic anemia, with an estimated risk of 1 in 5000 to 1 in 8000 patients, and hepatic failure, with an estimated risk of 1 in 26,000 to 1 in 54,000 patients.
Both are unlikely after 1 year of treatment, and aplastic anemia has not been reported in patients younger than 13 years of age.
These two serious adverse effects have resulted in a boxed warning suggesting that felbamate should be used only for severe epilepsy where treatment benefits outweigh the risk.

It is recommended to check a complete blood cell count and liver function test prior to starting felbamate and to repeat the tests every 2 weeks in the first 6 months of treatment

Question 35

Gabapentin: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions 5) dosage

Answer 35

1) Gabapentin binds to the alpha-2-delta subunit of voltage-gated calcium channels, reducing the influx of calcium and associated neurotransmitter release under hyperexcitable conditions

2) Low
3) Short
4) No (potential antacid interference with its absorption)
5) Oral: Initial: 300 mg 3 times daily; increase dose based on response and tolerability. Usual dosage: 300 to 600 mg 3 times daily

Question 36

Gabapentin: 1) efficacy 2) adverse effects 3) place in therapy

Answer 36

1) Gabapentin is a narrow-spectrum agent against focal seizures

2)
- CNS and respiratory depression
- Hypersensitivity reactions (immediate)
- Hypersensitivity reactions (delayed)
- Neuropsychiatric effects
motional lability; hostility (eg, aggressive behaviors); changes in behavior and thinking (eg, concentration problems, changes in school performance); and hyperkinetic muscle activity (eg, restlessness, hyperactivity), agitation
- Suicidal ideation and tendencies
- Ataxia, dizziness, fatigue
- Weight gain

3) Gabapentin can be used as adjunctive treatment for focal seizures.
It is often chosen for its anecdotal benefit in the treatment of headache and other pain and its benefit for sleep.
Although approved in Europe for initial monotherapy, a large randomized comparative trial found it less effective than lamotrigine

Question 37

Pregabalin: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions 5) dosage

Answer 37

1) Pregabalin is structurally related to gabapentin and has a similar mechanism of action (voltage-gated calcium channels)

2) Low
3) Short
4) No
5) Oral: Initial: 150 mg/day in 2 or 3 divided doses; may increase based on response and tolerability at weekly intervals up to a maximum dose of 600 mg/day.

Question 38

Pregabalin: 1) efficacy 2) adverse effects 3) place in therapy

Answer 38

1) Pregabalin is a narrow-spectrum drug against focal seizures.
The official FDA epilepsy indication is adjunctive therapy for adult patients with partial onset seizures.
Like gabapentin, it may exacerbate generalized myoclonic and absence seizures.
It also has an FDA indication for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia

2) The adverse effects of pregabalin include dizziness, somnolence, increased appetite, weight gain, and peripheral edema.
Myoclonus may occur with higher doses in some individuals

3) Pregabalin is indicated as adjunctive therapy for focal seizures.
It was inferior to lamotrigine as first-line therapy and should probably not be used as a first-line treatment

Question 39

Pregabalin (Lyrica) indication

Answer 39

Νευροπαθητικός πόνος
Το Lyrica ενδείκνυται για τη θεραπεία του περιφερικού νευροπαθητικού πόνου σε ενήλικες.

Επιληψία
Το Lyrica ενδείκνυται ως συµπληρωµατική θεραπεία σε ενήλικες µε εστιακές επιληπτικές κρίσεις µε ή χωρίς δευτερογενή γενίκευση.

Question 40

Lamotrigine: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 40

1) Lamotrigine blocks sodium channels, like phenytoin and carbamazepine, but must have other unrecognized actions to explain efficacy against absence seizures

2) Intermediate
3) Intermediate
4) Moderate

Question 41

Lamotrigine: 1) efficacy 2) dosage

Answer 41

1) Lamotrigine is a broad-spectrum AED
It is less effective against generalized absence seizures than valproate and ethosuximide.
It may be effective against myoclonic seizures in some patients but may exacerbate these seizures in others.
Lamotrigine also has an FDA indication for maintenance treatment in bipolar I disorder

2)
Patients not taking interacting medications:
Initial:
Weeks 1 and 2: 25 mg once daily; increase based on response and tolerability as follows:
Weeks 3 and 4: 50 mg/day in 1 to 2 divided doses based on chosen formulation;
Week 5 and beyond: increase by 50 mg/day every 1 to 2 weeks. Usual maintenance dose: 225 to 375 mg/day in 2 divided doses (immediate release) or 300 to 400 mg once daily (extended release)
Λόγω του κινδύνου εµφάνισης εξανθήµατος δεν πρέπει να γίνεται υπέρβαση της αρχικής δόσης και της επακόλουθης αύξησης της δοσολογίας

Question 42

Lamotrigine: 1) adverse effects 2) place in therapy

Answer 42

1)
- Aseptic meningitis
- Blood dyscrasias
agranulocytosis, neutropenia, pancytopenia, and pure red cell aplasia. Aplastic anemia has also been reported
- Hypersensitivity reactions (delayed)
- Hemophagocytic lymphohistiocytosis
- Suicidal ideation/tendencies

2) Lamotrigine is an important first-line AED for focal seizures and generalized tonic-clonic seizures.
Several comparative trials have favored lamotrigine over other AEDs for focal seizures in the balance of tolerability and efficacy.
However, it was inferior to valproic acid for idiopathic generalized epilepsy and inferior to ethosuximide for generalized absence seizures.
Lamotrigine is less sedating and has fewer cognitive adverse effects than traditional AEDs.
Its monotherapy use is associated with one of the lowest rates of teratogenicity, favoring its use in women of childbearing age!!
Lamotrigine may have pharmacodynamic interactions with other classic sodium channel blockers, resulting in adverse effects at lower than expected serum concentrations.
However, its combination with valproate can be synergistic, with greater efficacy than predicted

Question 43

Lamotrigine (Lamictal) indication

Answer 43

Ενήλικες και έφηβοι ηλικίας 13 ετών και άνω-
Συμπληρωματική θεραπεία ή μονοθεραπεία για την αντιμετώπιση εστιακών και γενικευμένων επιληπτικών κρίσεων, συμπεριλαμβανομένων των τονικο-κλονικών επιληπτικών κρίσεων
- Κρίσεις που σχετίζονται με το σύνδρομο Lennox-Gastaut.
Το Lamictal χορηγείται ως συμπληρωματική θεραπεία, αλλά μπορεί να είναι το αρχικό αντιεπιληπτικό φάρμακο με το οποίο θα αρχίσει η θεραπεία στο σύνδρομο Lennox-Gastaut.

Παιδιά και έφηβοι ηλικίας 2 έως 12 ετών
- Συμπληρωματική θεραπεία για την αντιμετώπιση εστιακών και γενικευμένων επιληπτικών κρίσεων, συμπεριλαμβανομένων των τονικο-κλονικών επιληπτικών κρίσεων και των κρίσεων που σχετίζονται με σύνδρομο Lennox-Gastaut.
- Μονοθεραπεία των τυπικών αφαιρέσεων!

Διπολική διαταραχή

Question 44

Which factors affect lamotrigine clearance

Answer 44

Lamotrigine clearance is decreased by valproate and increased by estrogen and pregnancy!! as well as by enzyme inducers

Question 45

Topiramate: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions 5) dosage

Answer 45

1) Topiramate has multiple mechanisms of action, including antagonism of AMPA/kainate receptors, augmentation of GABA activity, blocking of voltage-gated sodium channels and weakly inhibits carbonic anhydrase

2) Low
3) Intermediate
4) No/ minimal
5)
Monotherapy: Oral: Initial: 50 mg/day; increase dose in 50 mg increments at weekly intervals based on response and tolerability up to 200 mg/day in 1 to 2 divided doses based on chosen formulation; thereafter, may further increase in 100 mg increments at weekly intervals up to 400 mg/day in 1 to 2 divided doses based on chosen formulation.

Adjunctive therapy: Oral: Initial: 25 to 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation.

Question 46

Topiramate: 1) efficacy 2) place in therapy

Answer 46

Topiramate is a broad-spectrum AED effective against focal and generalized tonic-clonic seizures.
A pilot trial suggested it is not effective for generalized absence seizures.
It is FDA approved for migraine prophylaxis and as a weight-loss preparation in combination with phentermine.
It is also frequently used off-label for bipolar disorder

2) Although topiramate is FDA approved for initial monotherapy for focal seizures and generalized tonic-clonic seizures, it is not a drug of first choice because of its cognitive adverse effects, unless its use is justified by comorbidity, such as headache or obesity.
It is effective as adjunctive therapy for focal and generalized seizures and Lennox-Gastaut syndrome

Question 47

Topiramate (Topamac) indication

Answer 47

Μονοθεραπεία σε ενήλικες, εφήβους και παιδιά ηλικίας άνω των 6 ετών με εστιακές επιληπτικές κρίσεις με ή χωρίς δευτερογενώς γενικευμένες κρίσεις και πρωτογενώς γενικευμένες τονικοκλονικές κρίσεις

Συμπληρωματική θεραπεία σε παιδιά ηλικίας 2 ετών και άνω, εφήβους και ενήλικες με εκδήλωση εστιακών επιληπτικών κρίσεων με ή χωρίς δευτερογενή γενίκευση ή πρωτογενώς γενικευμένους τονικοκλωνικούς σπασμούς και για τη θεραπεία των κρίσεων που σχετίζονται με το σύνδρομο Lennox-Gastaut.

Η τοπιραμάτη ενδείκνυται για χρήση σε ενήλικες για την προφύλαξη της ημικρανίας μετά από προσεκτική εκτίμηση των πιθανών εναλλακτικών θεραπευτικών επιλογών.

Question 48

Topiramate: adverse effects

Answer 48

• CNS effects/cognitive dysfunction
  dose-related sedative effects (eg, dizziness, drowsiness, fatigue). Additionally, topiramate has been associated with both short-term and long-term cognitive dysfunction in both children and adults, including disturbance in attention, memory impairment, and language problems.
  Topiramate-associated cognitive dysfunction includes declines in verbal fluency, attention/concentration, processing speed, language skills, perception, working memory, reduced IQ, poor verbal fluency, abnormal thinking, and word-finding deficits. Topiramate is also associated with psychiatric disturbances (eg, aggressive behavior, mood disorder, anxiety, depression, exacerbation of depression), particularly in patients with previous history of depression or cognitive adverse reactions.
  Topiramate is also associated with paresthesia.
• Metabolic acidosis
  Decreased bone mineral density (BMD)
  Linear skeletal growth rate below expectation
• Nephrolithiasis
• Ocular effects
  acute myopia with secondary angle-closure glaucoma in children and adults.
  Also associated with choroidal effusion and visual field defect, scotoma, and maculopathy, which may occur without elevation of intraocular pressure.
  Bilateral hypopyon uveitis and choroidal detachment
• Oligohidrosis/hyperthermia
• Suicidal ideation/tendencies
• Weight loss/anorexia

Question 49

Tiagabine: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 49

1) Tiagabine inhibits GABA reuptake at the synapse

2) It is 96% protein bound, but this is of limited importance because dosing decisions are not dependent on the level, and its serum concentration is so low that it does not significantly compete for protein binding
3) Short (<10 hours)
4) High

Question 50

Tiagabine: 1) efficacy 2) adverse effects 3) place in therapy

Answer 50

1) Tiagabine has a narrow spectrum of efficacy against focal seizures only.
It may exacerbate generalized absence and myoclonic seizures.
It is used off-label in the management of spasticity in multiple sclerosis, in the treatment of addiction, and to increase deep sleep proportion

2) The most common adverse effects are dizziness, asthenia, nervousness, tremor, depression, and emotional lability, which are more common during titration.
Tiagabine may be associated with dose-related episodes of nonconvulsive status epilepticus or encephalopathy, which may occur even in the absence of epilepsy

3) Tiagabine should be reserved for use as adjunctive therapy for focal seizures

Question 51

Levetiracetam: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 51

1) The precise mechanism by which levetiracetam exerts its antiseizure effect is unknown.
However, several studies have suggested the mechanism may involve one or more of the following central pharmacologic effects:
- inhibition of voltage-dependent N-type calcium channels
- facilitation of GABA-ergic inhibitory transmission through displacement of negative modulators
- reduction of delayed rectifier potassium current
- and/or binding to synaptic proteins which modulate neurotransmitter release (binding to the synaptic vesicle protein SV2A)

2) Very low
3) Short
4) No

Question 52

Levetiracetam: 1) efficacy 2) adverse effects 3) place in therapy

Answer 52

1) Levetiracetam is a broad-spectrum drug, effective against focal seizures, generalized tonic-clonic seizures, and generalized myoclonic seizures

2)
- CNS depression
asthenia, ataxia, fatigue, dizziness, and somnolence
- Hypersensitivity reactions (delayed)
- Psychiatric and behavioral abnormalities
Psychotic symptoms, paranoid ideation, hallucinations, and behavioral problems (including aggressive behavior, agitation, anger, anxiety, apathy, confusion, depersonalization, depression, emotional lability, hostility, dyskinesia, irritability, nervousness, neurosis, and personality disorder) may occur in adult and pediatric patients; dose reduction or discontinuation may be required.
Suicidal ideation and suicidal tendencies

3) Although levetiracetam is not FDA approved for monotherapy in the United States, it is used widely as a first-line treatment for focal and generalized tonic-clonic seizures and is approved for initial monotherapy in Europe.
It is also an excellent adjunctive treatment in view of its safety and absence of interactions.
The IV preparation has been used as a second-line agent in the treatment of status epilepticus

Question 53

Levetiracetam (Keppra) indication

Answer 53

Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy.

Keppra is indicated as adjunctive therapy:

• in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
• in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

Question 54

Brivaracetam: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 54

1) Brivaracetam is structurally related to levetiracetam and has a similar mechanism of action through binding to SV2A but with approximately 20-fold higher affinity and greater selectivity

2) Low
3) Short
4) Moderate

Question 55

Brivaracetam: 1) efficacy 2) adverse effects 3) place in therapy

Answer 55

1) Although brivaracetam has a broad spectrum of efficacy in preclinical models, human Class I trials have only been conducted in patients with focal seizures

2) The most commonly reported adverse experiences occurring more often than placebo were somnolence, dizziness, fatigue and irritability

3) Brivaracetam is FDA approved for the treatment of partial onset seizures in patients 16 years of age and older.
This indication includes monotherapy and adjunctive use of the drug, although it has not specifically undergone monotherapy trials.
One small open-label study suggested that behavioral adverse effects from levetiracetam may improve after switching to brivaracetam

EMA only adjunctive

Question 56

Briviact indication

Answer 56

Briviact is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

Question 57

Brivaracetam pharmacokinetic and drug interactions

Answer 57

Brivaracetam has more interactions than levetiracetam.
Its clearance is increased by enzyme inducers.
It may increase carbamazepine epoxide and may also increase phenytoin concentration by up to 20%

Question 58

Zonisamide: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 58

1) Zonisamide is structurally related to sulfonamides.
It has multiple mechanisms of action, including blocking T-type calcium channels (predictive of efficacy against absence seizures), blocking sodium channels, and weak inhibition of carbonic anhydrase activity

2) Low
3) Long
4) Moderate

Question 59

Zonisamide: 1) efficacy 2) adverse effects 3) place in therapy

Answer 59

1) Zonisamide is considered a broad-spectrum AED, although Class I trials have only been conducted in patients with focal seizures

2) Irritability, anorexia - weight loss!, kidney stones, restless legs
Significant CNS effects include psychiatric symptoms (eg, depression, psychosis), psychomotor slowing (eg, difficulty with concentration, speech or language problems), and fatigue or somnolence;
may occur within the first month of treatment

3) Zonisamide is indicated as initial monotherapy for focal seizures in Europe.
In Japan, it is also indicated as monotherapy for generalized seizures.
Zonisamide is rarely the first-choice agent for initial monotherapy because of its cognitive adverse effects.
However, its long half-life could be an advantage, reducing the impact of a missed dose

Question 60

Zonisamide (Zonegran) indication

Answer 60

Το Zonegran ενδείκνυται ως:
- μονοθεραπεία στην αντιμετώπιση των εστιακών επιληπτικών κρίσεων, με ή χωρίς δευτερογενή γενίκευση, σε ασθενείς με νεοδιαγνωσθείσα επιληψία
- πρόσθετη θεραπεία στην αντιμετώπιση των εστιακών επιληπτικών κρίσεων, με ή χωρίς δευτερογενή γενίκευση, σε ενήλικες, εφήβους και παιδιά ηλικίας 6 ετών και άνω

Πλεονέκτημα: Μπορεί να προτιμηθεί σε ασθενέις με επιληψία και νόσο του Πάρκινσον
Χορηγείται μία φορά την ημέρα

Question 61

Lacosamide: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 61

1) Lacosamide blocks sodium channels, enhancing slow inactivation, unlike most classic sodium channel blockers, which enhance fast sodium channel inactivation

2) Low
3) Intermediate
4) No/ Minimal

Question 62

Lacosamide: 1) efficacy 2) adverse effects 3) place in therapy

Answer 62

1) Lacosamide appears to be a narrow-spectrum AED against focal seizures.
However, preliminary data suggest that it does not exacerbate absence or myoclonic seizures

2)
- Cardiovascular effects
cardiac arrhythmias including, but not limited to bradycardia, atrioventricular block, and tachyarrhythmias such as atrial fibrillation, atrial flutter, and ventricular tachycardia
- CNS effects
dizziness, drowsiness, headache, and ataxia are common and expected adverse reactions that may occur with lacosamide
Other CNS-related adverse reactions may include confusion, cognitive dysfunction, memory impairment, paresthesia, and sleep disturbance
- Hypersensitivity reactions (delayed)
- Suicidal ideation/tendencies

3) Lacosamide is indicated as monotherapy and as adjunctive therapy for focal seizures.
Several anecdotal reports also exist of efficacy in status epilepticus.
When lacosamide is used as adjunctive therapy, it may have greater efficacy and better tolerability if it is combined with a non–sodium channel drug

Question 63

Vimpat indication

Answer 63

Το Vimpat ενδείκνυται ως μονοθεραπεία για τη θεραπεία επιληπτικών κρίσεων εστιακής έναρξης με ή χωρίς δευτερογενή γενίκευση, σε ενήλικες, εφήβους και παιδιά από την ηλικία των 2 ετών που πάσχουν από επιληψία.

Το Vimpat ενδείκνυται ως συμπληρωματική αγωγή:

• για τη θεραπεία επιληπτικών κρίσεων εστιακής έναρξης με ή χωρίς δευτερογενή γενίκευση σε ενήλικες, εφήβους και παιδιά από την ηλικία των 2 ετών που πάσχουν από επιληψία.
• για τη θεραπεία των πρωτογενώς γενικευμένων τονικο-κλονικών επιληπτικών κρίσεων σε ενήλικες, εφήβους και παιδιά από την ηλικία των 4 ετών που πάσχουν από ιδιοπαθή γενικευμένη επιληψία.

Question 64

Vigabatrin: mechanism of action

Answer 64

Vigabatrin is an irreversible inhibitor of GABA transaminase, resulting in accumulation of GABA

Question 65

Vigabatrin: 1) efficacy 2) adverse effects 3) place in therapy

Answer 65

1) Vigabatrin is a narrow-spectrum drug effective against focal seizures.
It may worsen absence and myoclonic seizures in idiopathic generalized epilepsy.
However, it is effective against infantile spasms, particularly in the presence of tuberous sclerosis

2) Permanent visual field defect (και γι αυτό δεν χρησιμοποιείται μακροχρόνια)

3) Vigabatrin use is reserved for adjunctive therapy in subjects who have failed several alternative treatments and monotherapy in infants with infantile spasms.
Because of the visual toxicity, periodic visual assessment is recommended at baseline and every 3 months, and treatment should be continued only if considerable benefit is observed in the first 3 months

Question 66

Rufinamide: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 66

1) Rufinamide is a sodium channel blocker, although additional mechanisms of action are likely

2) Intermediate
3) Short
4) Moderate

Question 67

Rufinamide: 1) efficacy 2) adverse effects 3) place in therapy

Answer 67

1) Rufinamide is a broad-spectrum AED, but its efficacy against focal seizures was not sufficient for an FDA indication

2) The adverse effects of rufinamide include dizziness, fatigue, somnolence, and headache. Vomiting may occur in children.
Rufinamide may cause a shortening of the QT interval

3) Rufinamide is FDA indicated as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome

Question 68

Perampanel: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 68

1) Perampanel is a selective noncompetitive AMPA glutamate receptor antagonist.

2) High
3) Long
4) Moderate

Question 69

Perampanel: 1) efficacy 2) adverse effects 3) place in therapy

Answer 69

1) Perampanel is effective for focal seizures and generalized tonic-clonic seizures

2) The adverse effects of perampanel include dizziness, somnolence, headache, fatigue, ataxia, and blurred vision. Aggression and hostility may occur (Behavioral changes were more common in patients with intellectual disability)

3)
Partial-onset seizures: Treatment of partial-onset seizures with or without secondarily generalized seizures as adjunct or monotherapy in patients with epilepsy who are ≥4 years of age.

Primary generalized tonic-clonic seizures: Treatment of primary generalized tonic-clonic seizures as adjunct therapy in patients with epilepsy who are ≥12 years of age.

Although there is no FDA indication for myoclonic seizures, several case reports and case series suggest particular efficacy in progressive myoclonic epilepsies, which are usually resistant to therapy

** EMA only adjunct

Question 70

Perampanel (Fycompa) indication

Answer 70

Το Fycompa ενδείκνυται για τη συμπληρωματική αντιμετώπιση των επιληπτικών κρίσεων εστιακής έναρξης με ή χωρίς δευτερογενώς γενικευμένες επιληπτικές κρίσεις σε ενήλικες και εφήβους ασθενείς ηλικίας από 12 ετών με επιληψία.

Το Fycompa ενδείκνυται για τη συμπληρωματική αντιμετώπιση των πρωτοπαθών γενικευμένων τονικοκλονικών κρίσεων σε ενήλικες και εφήβους ασθενείς ηλικίας από 12 ετών με ιδιοπαθή γενικευμένη επιληψία

Πλεονέκτημα: χορηγείται μία φορά την ημέρα (βράδυ)!

Question 71

Cannabidiol: 1) Mechanism of action 2) protein binding 3) half-life 4) potential for pharmacokinetic interactions

Answer 71

1) Its exact mechanisms of action are not known, but it may enhance GABA activity through allosteric modulation of the GABA-A receptor and enhancement of currents elicited by low GABA concentrations

2) High
3) Long
4) High

Question 72

Cannabidiol: 1) adverse effects 2) place in therapy

Answer 72

1) Its most common adverse effects are sedation, fatigue, decreased appetite, and diarrhea. It may produce an increase in liver enzymes, particularly when used in conjunction with valproate or with valproate and clobazam. Liver enzymes and total bilirubin levels should be obtained before treatment and at 1, 3, and 6 months after initiation of treatment

2) Cannabidiol is FDA indicated for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older based on blinded controlled trials. Open-label trials also suggest efficacy for other forms of epilepsy

Question 73

Cannabidiol (Epidyolex) indication

Answer 73

Το Epidyolex ενδείκνυται για χρήση ως επικουρική θεραπεία κρίσεων συσχετιζόμενων με το σύνδρομο Lennox-Gastaut ή το σύνδρομο Dravet σε συνδυασμό με κλοβαζάμη για ασθενείς ηλικίας 2 ετών και άνω.

Το Epidyolex ενδείκνυται για χρήση ως επικουρική θεραπεία κρίσεων συσχετιζόμενων με την οζώδη σκλήρυνση για ασθενείς ηλικίας 2 ετών και άνω.

Question 74

Cenobamate (Ontozry) indications

Answer 74

Το Ontozry ενδείκνυται για τη συμπληρωματική θεραπεία των επιληπτικών κρίσεων εστιακής έναρξης με ή χωρίς δευτερογενή γενίκευση σε ενήλικες ασθενείς με επιληψία που δεν έχουν ελεγχθεί επαρκώς παρά το ιστορικό θεραπείας με τουλάχιστον 2 αντιεπιληπτικά φαρμακευτικά προϊόντα.

Πλεονεκτήματα: Αποτελεσματικό στη φαρμακοανθεκτική επιληψία
Χορηγείται μία φορά την ημέρα

Question 75

Fenfluramine indications

Answer 75

Fintepla is indicated for the treatment of seizures associated with Dravet syndrome and Lennox Gastaut syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older